Direct C

Letter Cite This: Org. Lett. 2018, 20, 6027−6032

pubs.acs.org/OrgLett

Palladium-Catalyzed Domino Allenamide Carbopalladation/Direct C−H Allylation of Heteroarenes: Synthesis of Primprinine and Papaverine Analogues Jonathan Hédouin,† Cédric Schneider,† Isabelle Gillaizeau,*,‡ and Christophe Hoarau*,† †

INSA Rouen, CNRS, COBRA, Normandie Univ, UNIROUEN, 76000 Rouen, France CNRS, ICOA, Université d’Orléans, UMR 7311, 45067 Orléans, France

‡

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S Supporting Information *

ABSTRACT: Palladium-catalyzed intramolecular carbopalladation onto allenamides completed by direct C−H allylation of heterocycles is studied. The domino construction/ heteroarylation of isoquinolone process is first achieved. A general three-step one-pot strategy, involving in situ generation of allenamide, π-allyl-Pd complex generation, and interception with heteroarenes, has been subsequently set up. This methodology has been extended to the construction/ heteroarylation of indoles, dihydroquinolines, isoquinolin(on)es, and medium-sized nitrogen heterocycles, which are known to be key challenging structural motifs with pharmaceutical significance.

T

he rapid construction of molecular complexity from readily accessible starting material is, inarguably, a subject of central importance in modern organic synthesis. Considerable progress has been made in this area by taking advantage of transition-metal-catalyzed domino reactions, which have proved to be valuable tools for sustainable synthesis and for the powerful construction of complex molecules through the formation of multiple bonds in one sequence.1 The domino construction/functionalization of standard important classes of nitrogen-containing heterocycles has been actively studied according to the following pathway: (a) intramolecular or intermolecular carbopalladation of halogenated (hetero)aromatics onto standard allenamide, then (b) the termination step involving the capture of π-allyl-Pd(II) intermediates with organometallics, nucleophiles, or oxidants (see Figure 1).2 An ecofriendly, step- and atom-economical added value is to manage the terminal cross-coupling step through direct C−H functionalization reactions.3,4 Although carbopalladation/intramolecular direct C−H functionalization sequences have been actively developed,3−5 intermolecular sequences remain sparsely proposed to date. As remarkable examples, the Fagnou, Van der Eycken, Liang and Zhu groups reported the interception of σ-alkyl/vinyl-Pd(II) intermediates with heterocycles.6 The present work proposes original sequences of carbopalladation of ortho-halogenoallenamides completed by intermolecular direct C−H allylation of azoles (see Figure 1), which are important structural motifs found in many pharmaceuticals, agrochemicals, and natural products.7 This methodology offers an original step-economical and regiocontrolled synthetic pathway to bis-heteroaryl methylenes embedded in various families of 5-, 6-, 7- and 8-membered nitrogen heterocycles, such as indole, isoquinolin(one), © 2018 American Chemical Society

Figure 1. Standard and novel domino reactions with orthohalogenoallenamides through carbopalladation and interception of π-allyl Pd(II) complexes.

azepine, or azocine, which are known to be key challenging structural motifs with pharmaceutical significance.8−11 Despite the considerable achievement made in direct C−H (hetero)arylation, alkenylation, alkynylation, and alkylation of azoles,12,13 this work proposes original examples of direct C−H allylation of heterocycles based on pioneer developments using allyl phosphates and halides as coupling partners under copper catalysis.14 Our initial investigations focused on the Pd-catalyzed domino intramolecular carbopalladation/C−H allylation of 2phenyl-1,3,4-oxadiazole (3A) with ortho-halogenoallenamides Received: July 26, 2018 Published: September 25, 2018 6027

DOI: 10.1021/acs.orglett.8b02365 Org. Lett. 2018, 20, 6027−6032

Letter

Organic Letters 2aa−2ac, which were standardly prepared from orthohalogenopropargylbenzamides 1aa−1ac through a basic treatment at room temperature.2,15 The results are summarized in Table 1. Starting from 2aa (X = I), the first use of standard

Scheme 1. One-Pot Isomerization/Carbopalladation/C−H Allylation

Table 1. Optimization of the Domino Carbopalladation/C− H Allylation Processa

entry

ligand

X

solvent

yieldb (%)

1 2 3 4 5 6c 7c 8c

PCy3·HBF4 PCy3·HBF4 PCy3·HBF4 PMetBu2·HBF4 PtBu3·HBF4 PMetBu2·HBF4 PMetBu2·HBF4 PMetBu2·HBF4

I I I I I I Br Cl

1,4-dioxane toluene DMAc 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane

57 51 32 65 60 72 66 n.r.

explored from ortho-iodoallenamides 2 (see Scheme 2, Method A) using variously substituted 5-arylated 1,3,4-oxadiazoles (3) as coupling partners. Overall, the selective capturing of the πallyl-Pd(II) intermediate with heterocycles was successfully achieved, regardless of the electronic effect or the substitution pattern on the two aromatic units of coupling partners 3 and 2, affording 4-oxadiazolylmethyl isoquinolones 4aB−4aH, 4bA, 4cG, 4dC, and 4eD in fair yields. We further examined the selective direct C2−H allylation of various less-acidic 1,3diazoles (3I−3K). In this case, replacing 1,4-dioxane by toluene facilitated the coupling with benzoxazole or ethyl oxazole-4-carboxylate to produce the corresponding 4-(benz)oxazolylmethyl isoquinolinones 4aI and 4aK, albeit in low yields. Moreover, the domino coupling of 2aa was successfully performed with the tert-butyl thiazole-4-carboxylate in morepolar solvent (i.e., DMF), leading to the desired thiazolylmethylisoquinolinone 4aJ in 22% yield. It is also noteworthy that the most acidic pentafluoarene, 3L, which was previously demonstrated to be suitable for C−H allylation,20 was successfully employed as a coupling partner in the palladiumcatalyzed domino reaction from 2aa only under CuI assistance, leading to the expected allylated pentafluoroarene 4aL in good yield (52%). In order to enhance the practical usefulness of our method, we sought to evaluate the possibility of performing a one-pot sequential tBuOK-catalyzed allenamide generation/ Pd-catalyzed domino cross-coupling with 3A from readily available propargylbenzamides 1 (Scheme 1). Interestingly, the treatment of ortho-iodopropargylbenzamide 1aa with 30 mol % tBuOK, for the in situ generation of the allenamide 2aa,21 followed by the formation of PivOK with the addition of PivOH (0.3 equiv) before the domino C−H coupling, was immediately conclusive. Indeed, this one-pot pathway provided the expected oxadiazolylmethylindole 4aA in good yield (54%), close to the overall 62% yield previously obtained through the two-step sequential pathway. Based on this result, we decided to evaluate systematically the three-step one-pot sequence, and the results are depicted in Scheme 2 (Method B). Starting from propargylbenzamide 1aa and using 1,3,4-oxadiazole 3A−3H as coupling partners, a broad set of 4(1,3,4-oxadiazolyl)methyl isoquinolones 4aB−4aH were successfully produced within the three-step sequential protocol (Method B) in only slightly lower yields than those observed from allenamides 2aa (Method A). Using the same one-pot procedure, fair yields were also obtained for the synthesis of variously substituted 4-(1,3,4-oxadiazolyl)methyl isoquinolones 4bA, 4cG, 4dC, and 4eD. In addition, the coupling of less-acidic 1,3-diazoles 3I−3K, as well as the pentafluoroarene 3L, was successfully performed, leading to the corresponding

a

Reaction conditions: 2 (0.435 mmol), 3A (1.5 equiv), Pd(OAc) (10 mol %), ligand (20 mol %), Cs2CO3 (3 equiv), solvent (1 mL), in a sealed tube at 110 °C for 12 h. bYield based on isolated 4aA after purification by chromatography. c0.3 equiv of PivOH was added.

Pd(OAc)2 precatalyst associated with PCy3·HBF4 as a ligand in the presence of 3 equiv of Cs2CO3 afforded the heteroarylmethylisoquinolone 4aA in 57% yield (see Table 1, entry 1). Various bases were tested and turned out to be less efficient.16 While the reaction was less efficient in more-polar DMAc solvents (32%), a similar performance was obtained in toluene, providing 4aA in 51% yield (see Table 1, entries 2 and 3). More steric hindered and electron-donor alkyl phosphine ligands, PtBu3·HBF4 or PMetBu2·HBF4, showed superior reactivity, affording 4aA in better yields, from 60% to 65%, respectively (see Table 1, entries 4 and 5). The beneficial use of PivOH as an additive, which has been previously shown to stabilize the π-allyl Pd(II) complex in transition metalcatalyzed direct allylation,17 gave the best result, affording 4aA in 72% yield (see Table 1, entry 6). Under these optimized conditions, we demonstrated that this domino allylation sequence could be successfully performed from the ortho-bromoallenamide 2ab, leading to 4aA in fair yield (66%) (see Table 1, entry 7). However, no reaction occurred from the ortho-chloroallenamide 2ac (see Table 1, entry 8). Note that only one regioisomer was identified by single-crystal X-ray structure determination; the regioisomer arising from heteroarylation at the α-position of the π−allyl-Pd(II) complex was not observed on the NMR spectrum of the crude reaction. At this stage, we investigated the ability of the propargylamide 1aa to react with 3A either by Cs2CO3-promoted isomerization, followed by direct C−H allylation reaction,18 or through intramolecular carbopalladation/exo-dig direct C−H alkenylation, followed by [1,3]-H-shift,19 to give the desired product 4aA. In order to preclude both scenarios, a control experiment was performed by reacting the propargylamide 1aa with 3A under our optimized conditions (see Scheme 1). However, no annulating product 4aA was obtained. With the optimized protocol in hand, the scope of the domino carbopalladation/intermolecular C−H allylation was 6028


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Organic Letters

Scheme 2. Synthesis of 1,3-diazolylmethylisoquinolinones 4 by Domino Intermolecular Carbopalladation/C−H Allylation (Method A) or One-Pot Sequential Allenamide Generation/Domino Process (Method B)

a

Toluene was used instead of 1,4-dioxane. bDMF was used instead of 1,4-dioxane. cCuI (30 mol %) was added.

on the synthesis of indolyl[1,3-diazolyl]methylene as the framework of pimprinine that displays antifungal activities.22 To this end, the one-pot three-step procedure (Method B) was envisaged to avoid purification and stability issues. Interestingly, three N-Boc indolyl-1,3-azolylmethyles 5fA, 5fD, and 5fK were successfully prepared from the corresponding N-Boc ortho-iodopropargylamide 1f using 1,3,4-oxadiazoles, 3A and 3D, and ethyl oxazole-4-carboxylate 3K as coupling partners in a range of yields of 22%−38% over three steps (see Scheme 3). The heteroarylation was regioselective at the γ-position of the π-allyl-Pd(II) complex. Moreover, two analogues of primprinine 5gA and 5gB were obtained from the acetamide 2g in good yields (40%−42%) within a four-step one-pot process including a spontaneous N-deprotection step. Pursuing our investigations into the construction/heteroarylation of isoquinolines, the one-pot three-step sequence was then envisaged with N-(2-iodobenzyl)prop-2-yn-1-amine (2h) and 5-phenylated 1,3,4-oxadiazole (3A) as coupling partners. The expected heteroarylmethyldihydroquinoline (6hA) was isolated in 56% yield. However, it turned out to be highly unstable in air, leading to rapid degradation. To circumvent this instability issue, an additional treatment with DDQ23 as oxidant was included in our one-pot strategy, leading to the 1,3,4-oxadiazolylmethylisoquinolin 7hA in 23% yield over four steps. This product can be considered as a novel 1,3,4oxadiazole analogue of papaverine (see Scheme 3).24 Finally, to further evaluate the scope of the strategy, we turned our attention to the construction/heteroarylation of innovative medium-sized nitrogen heterocycles, which remains currently very sparsely explored. Interestingly, the one-pot strategy developed above was successfully applied for the synthesis of stable heteroarylmethylated dihydro-1H-benzo[d]azepine 8iA and 8iJ, as well as tetrahydro-1H-benzo[d]azocine 9jA in a yield range from 20% to 70%, starting with N-(3-phenylethyl)prop-2-yn-1-amine (1i) and N-(3-phenylpropyl)prop-2-yn-1amine (1j), respectively. A catalytic cycle based on experimental results and previous reports on cyclocarbopalladation with allenamide is proposed

4-(1,3-diazolyl)methyl isoquinolinones 4aI−4aK and 4(pentafluoroaryl)methy isoquinolone 4aL in satisfactory yields. At this stage, we further investigated the construction/ heteroarylation of various families of 5-, 6-, and highmembered nitrogen-containing heterocycles. We first turned our attention to the indole scaffold, a privileged structure occurring in numerous natural products and biologically active molecules designed for agricultural and medicinal applications (see Scheme 3).9 In particular, we focused our methodology Scheme 3. Scope of the One-Pot tBuOK-Mediated Allenamide Generation Followed by Pd-Catalyzed Carbopalladation/Direct C−H Allylation of 1,3-Diazoles

a

Additional treatment was required using DDQ in MeOH at reflux for 2 h. 6029


Letter

Organic Letters in Scheme 4.2 Initially, the oxidative addition of allenamide 2 by the ligated Pd(0) species generates the Pd(II) complex A.

methodology involving the consecutive formation of C(sp2)− C(sp2) and C(sp3)−C(sp2) bonds through trapping a σ-allylPd(II) intermediate with (oxa)diazoles constitutes a straightforward and general route to prepare a great variety of bisheteroarylmethyle frameworks.

Scheme 4. Proposed Mechanistic Pathway

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02365. Experimental procedures, characterization data of new compounds, and copies of 1H and 13C NMR spectra (PDF) Accession Codes

CCDC 1822929 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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The subsequent cyclocarbopalladation step leads to the πallylpalladium intermediate B. The latter then rapidly undergoes an exothermic inner-sphere pivalate-halide exchange,25,17 leading to the more stable and less electron-rich πallylpalladium C. The next step concerns heterocycle C−H activation by the π-allylpalladium system. In agreement with previous observations, Grigg’s group demonstrated that an outer sphere nucleophilic attack is only favored from a halogenated (π-allyl)Pd complex using Ag2CO3 as an additive for the generation of a highly electrophilic and cationic (πallyl)Pd system.26 In addition, the branched product can be expected under this typical charge-controlled outer-sphere mechanism. In the present case, the employment of pivalate, combined with the PMetBu2·HBF4, electron-rich phosphine as ligand significantly decreases the positive charge of the (π-allyl) Pd complex C. As an additional experiment, the reaction was found to be fully inhibited in the presence of the Ag2CO3 additive with or without Cs2CO3.16 Thus, an SN2-type attack of a C2-metalated heterocycle on the (π-allyl)Pd complex C is precluded in favor of inner-sphere based-mediated concerted or carbanionic-type metalation deprotonation of 1,3-diazoles.12e,25b,27 It proceeds by generating a second heteroaryl (πallyl)Pd complex (D), which delivers the expected product through a final reductive elimination step while regenerating the Pd(0) catalyst. In summary, we have first reported an original Pd-catalyzed domino carbopalladation of allenamides/direct C−H allylation of (oxa)diazoles. Simultaneously, a one-pot strategy over three steps, including the in situ generation of allenamide in the domino process, was also developed to avoid allenamide stability issues. The two approaches were first validated and then applied to the design of a novel library of 3heteroarylmethylisoquinolinones, which is a key structural motif with potential pharmaceutical significance. This methodology was then successfully expanded to the construction/ heteroarylation of indole, dihydroquinoline, and isoquinoline, as well as original medium-sized nitrogen heterocycles, 7- and 8-membered azepine and azocine derivatives. As an application, three structural analogues of papaverin and pimprinine were prepared. Therefore, this construction/heteroarylation

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (I. Gillaizeau). *E-mail: [email protected] (C. Hoarau). ORCID

Cédric Schneider: 0000-0002-5128-5646 Isabelle Gillaizeau: 0000-0002-7726-3592 Christophe Hoarau: 0000-0001-9668-9970 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work has been partially supported by INSA Rouen, Rouen University, CNRS, EFRD, European INTERREG IV A France (Channel) and Labex SynOrg (No. ANR-11-LABX-0029). We also thank the CRIHAN for software optimization and technical support.

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REFERENCES

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(7) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, Ed.; Wiley−VCH: Weinheim, Germany, 2003. (b) Palmer, D. C. Oxazoles: Synthesis Reactions and Spectroscopy, Vol 1; Wiley: Hoboken, NJ, USA, 2003. (c) Turchi, I. J.; Dewar, M. J. S. Chemistry of Oxazoles. Chem. Rev. 1975, 75, 389. (d) Yeh, V. S. C. Recent Advances in the Total Syntheses of Oxazole-Containing Natural Products. Tetrahedron 2004, 60, 11995. (e) Ezzili, C.; Mileni, M.; McGlinchey, N.; Long, J. Z.; Kinsey, S. G.; Hochstatter, D. G.; Stevens, R. C.; Lichtman, A. H.; Cravatt, B. F.; Bilsky, E. J.; Boger, D. L. Reversible Competitive αKetoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Constraints in the Acyl Side Chain: Orally Active, Long-Acting Analgesics. J. Med. Chem. 2011, 54, 2805. (f) Jin, Z. Nat. Prod. Rep. 2013, 30, 869. (g) Parker, J. E.; Warrilow, A. G.; Price, C. L.; Mullins, J. G.; Kelly, D. E.; Kelly, S. L. Resistance to Antifungals that Target CYP51. J. Chem. Biol. 2014, 7, 143. (8) Isoquinolones are important structural motifs in natural products and drugs; see: (a) Lewis, J. R. Amaryllidaceae and Sceletium Alkaloids. Nat. Prod. Rep. 1994, 11, 329. (b) Cappelli, A.; Pericot Mohr, G.; Giuliani, G.; Galeazzi, S.; Anzini, M.; Mennuni, L.; Ferrari, F.; Makovec, F.; Kleinrath, E.; Langer, T.; Valoti, M.; Giorgi, G.; Vomero, S. Further Studies on Imidazo[4,5-b]pyridine AT1 Angiotensin II Receptor Antagonists. Effects of the Transformation of the 4-Phenylquinoline Backbone into 4-Phenylisoquinolinone or 1Phenylindene Scaffolds. J. Med. Chem. 2006, 49, 6451. (c) Martin, N. M. B.; Smith, G. C. M.; White, C. R.; Newton, R. F.; Douglas, D. G.; Eversley, P. J.; Whittle, A. J. Isoquinolinone Derivatives as Poly(ADPRibose)polymerase (PARP) Inhibitors. International Patent WO 02090334A, 2002. (9) Indoles are omnipresent in various bioactive compounds. For reviews, see: (a) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. A Review on Recent Developments of Indole-Containing Antiviral Agents. Eur. J. Med. Chem. 2015, 89, 421. (b) Singh, T. P.; Singh, O. M. Recent Progress in Biological Activities of Indole and Indole Alkaloids. MiniRev. Med. Chem. 2017, 18, 9 and references cited therein . (10) For a review on the biological activities of quinolone derivatives, see: Kumar, S.; Bawa, S.; Gupta, H. Biological Activities of Quinoline Derivatives. Mini-Rev. Med. Chem. 2009, 9, 1648. (11) Annulated azocine and azepine motifs are found in many natural products with a range of potentially useful bioactivities; see: (a) Young, I. S.; Kerr, M. A. Total Synthesis of (+)-Nakadomarin A. J. Am. Chem. Soc. 2007, 129, 1465. (b) Alvarez, M.; Joule, A. The Alkaloids. In Chemistry and Biology, Vol. 57; Academic Press: New York, 2001, 235. (c) Heterocycles in Natural Product Synthesis; Majumdar, K. C.; Chattopadhyay, S. K., Eds.; Wiley−VCH: Weinheim, Germany, 2011; 537. (d) Bremner, B.; Samosorn, S. Comprehensive Heterocyclic Chemistry III, Vol. 13; Elsevier: Amsterdam, 2008, 1. (12) For recent reviews of C−H arylation of azoles, see: (a) Alberico, D.; Scott, M. E.; Lautens, M. Aryl−Aryl Bond Formation by Transition-Metal-Catalyzed Direct Arylation. Chem. Rev. 2007, 107, 174. (b) Seregin, V. I.; Gevorgyan, V. Direct Transition MetalCatalyzed Functionalization of Heteroaromatic Compounds. Chem. Soc. Rev. 2007, 36, 1173. (c) Daugulis, O.; Do, H. Q.; Shabashov, D. Palladium- and Copper-Catalyzed Arylation of Carbon-Hydrogen Bonds. Acc. Chem. Res. 2009, 42, 1074. (d) Hirano, K.; Miura, M. Direct Carbon-Hydrogen Bond Functionalization of Heterocyclic Compounds. Synlett 2011, 2011, 294. (e) Verrier, C.; Lassalas, P.; Théveau, L.; Quéguiner, G.; Trécourt, F.; Marsais, F.; Hoarau, C. Recent Advances in Direct C-H Arylation: Methodology, Selectivity and Mechanism in Oxazole Series. Beilstein J. Org. Chem. 2011, 7, 1584. (f) Ackermann, L. Carboxylate-Assisted Transition-MetalCatalyzed C-H Bond Functionalizations: Mechanism and Scope. Chem. Rev. 2011, 111, 1315. (g) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51, 8960. (h) Miura, M.; Satoh, T.; Hirano, K. Development of Direct Aromatic Coupling Reactions by Transition-Metal Catalysis. Bull. Chem. Soc. Jpn. 2014, 87, 751. (i) Hirano, K.; Miura, M. Copper6031


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Organic Letters Mediated Direct Arylation of Azole Compounds. Top. Catal. 2014, 57, 878 and the references cited herein . (13) For recent reviews of C−H alkenylation and alkylation of azoles, see: (a) Messaoudi, S.; Brion, J. D.; Alami, M. TransitionMetal-Catalyzed Direct C-H Alkenylation, Alkynylation, Benzylation, and Alkylation of (Hetero)arenes. Eur. J. Org. Chem. 2010, 2010, 6495. (b) Rossi, R.; Bellina, F.; Lessi, M. Alkenylation Reactions of Heteroarenes by Transition Metal Catalysts. Synthesis 2010, 2010, 4131. (c) Ackermann, L. Metal-Catalyzed Direct Alkylations of (Hetero)arenes via C-H Bond Cleavages with Unactivated Alkyl Halides. Chem. Commun. 2010, 46, 4866. (14) Cu-catalyzed direct C−H allylation of azoles; see: (a) Makida, Y.; Ohmiya, H.; Sawamura, M. Regio- and Stereocontrolled Introduction of Secondary Alkyl Groups to Electron-Deficient Arenes through Copper-Catalyzed Allylic Alkylation. Angew. Chem., Int. Ed. 2012, 51, 4122. (b) Xie, W.; Chang, S. [Cu(NHC)]-Catalyzed C-H Allylation and Alkenylation of both Electron-Deficient and ElectronRich (Hetero)arenes with Allyl Halides. Angew. Chem., Int. Ed. 2016, 55, 1876. (c) Ohmiya, H.; Zhang, H.; Shibata, S.; Harada, A.; Sawamura, M. Construction of Quaternary Stereogenic Carbon Centers through Copper-Catalyzed Enantioselective Allylic Alkylation of Azoles. Angew. Chem., Int. Ed. 2016, 55, 4777. (15) Fretwell, P.; Grigg, R.; Sansano, J. M.; Sridharan, V.; Sukirthalingam, S.; Wilson, D.; Redpath, T. Palladium Catalyzed Tandem Cyclization-Anion Capture Processes. Part 4. Organotin(IV) transfer agents. Tetrahedron 2000, 56, 7525. (16) For full details concerning the screening of solvents, bases, palladium, ligands as well as additives, see the Supporting Information. (17) (a) Yu, Y.-B.; Fan, S.; Zhang, X. Copper- and PhosphineLigand-Free Palladium-Catalyzed Direct Allylation of ElectronDeficient Polyfluoroarenes with Allylic Chlorides. Chem. - Eur. J. 2012, 18, 14643. (b) Wang, H.; Schröder, N.; Glorius, F. Mild Rhodium(III)-Catalyzed Direct C-H Allylation of Arenes with Allyl Carbonates. Angew. Chem., Int. Ed. 2013, 52, 5386. (18) Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.; Worakun, T. Palladium Catalyzed Tandem Cyclization-Anion Capture Processes. Part 2. Cyclization onto Alkynes or Allenes with Hydride Capture. Tetrahedron 1996, 52, 11479. (19) Mondal, A.; Kundu, P.; Jash, M.; Chowdhury, C. PalladiumCatalysed Stereoselective Synthesis of 4-(Diarylmethylidene)-3,4Dihydroisoquinolin-1(2H)-ones: Expedient Access to 4-Substituted Isoquinolin-1(2H)-ones and Isoquinolines. Org. Biomol. Chem. 2018, 16, 963 (also see ref 16) . (20) Fan, S.; Chen, F.; Zhang, X. Direct Palladium-Catalyzed Intermolecular Allylation of Highly Electron-Deficient Polyfluoroarenes. Angew. Chem., Int. Ed. 2011, 50, 5918. (21) Allenamides could be prepared by the base-induced isomerization using a catalytic amount of t-BuOK; see: Shen, L.; Hsung, R. P. Highly Regioselective Radical Cyclizations of Allenamides. Org. Lett. 2005, 7, 775. (22) (a) Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward, E. M.; Stevenson, G.; Beer, H.; Stanton, J.; Watling, K. Novel 5-HT3 antagonists. Indole Oxadiazoles. J. Med. Chem. 1991, 34, 140. (b) Zhang, M.-Z.; Mulholland, N.; Beattie, D.; Irwin, D.; Gu, Y.-C.; Chen, Q.; Yang, G.-F.; Clough, J. Synthesis and Antifungal Activity of 3-(1,3,4-Oxadiazol-5-yl)-Indoles and 3-(1,3,4-Oxadiazol-5-yl)methylIndoles. Eur. J. Med. Chem. 2013, 63, 22. (23) Wada, Y.; Nishida, N.; Kurono, N.; Ohkuma, T.; Orito, K. Synthesis of a 3-arylisoquinoline Alkaloid, Decumbenine B. Eur. J. Org. Chem. 2007, 2007, 4320. (24) For papaverine analogues, see: Servin, A. L.; Christinaki, H.; Viel, C. Molecular Properties of the Papaverine Binding Sites Identified in Human Colonic Membranes with 6,7-Dimethoxy-4(4′-amino,3′-[125I]iodobenzyl)isoquinoline as Probe. Eur. J. Pharmacol. 1988, 149, 371. (25) (a) Kefalidis, C. E.; Baudoin, O.; Clot, E. DFT Study of the Mechanism of Benzocyclobutene Formation by Palladium-Catalysed

C(sp3)-H Activation: Role of the Nature of the Base and the Phosphine. Dalton Trans 2010, 39, 10528. (b) Théveau, L.; Querolle, O.; Dupas, G.; Hoarau, C. Ligand Controlled Orthogonal BaseAssisted Direct C−H Bond Arylation in Oxa(thia)zole-4-carboxylate series. New Insights in nCMD Mechanism. Tetrahedron 2013, 69, 4375. (26) (a) Grigg, R.; Sridharan, V.; Xu, L.-H. Palladium-Catalyzed Cyclization-Amination of Allenes - Effect of Base on Regioselectivity of Formation of Allylic Amines. J. Chem. Soc., Chem. Commun. 1995, 1903, 1903. (b) Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.; Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D. PalladiumCatalyzed Tandem Cyclization-Anion Capture Processes. Part 3. Organoboron Anion Transfer Agents. Tetrahedron 1997, 53, 11803. (27) For the direct C−H allylation of indoles from allenamides occurring through a CMD pathway, see: Cera, G.; Lanzi, M.; Balestri, D.; Della Ca’, N.; Maggi, R.; Bigi, F.; Malacria, M.; Maestri, G. Synthesis of Carbolines via Palladium/Carboxylic Acid Joint Catalysis. Org. Lett. 2018, 20, 3220.

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